Diabetes mellitus is a lifelong chronic disease with worldwide prevalence estimated at 180 million patients in 2007. The importance of transcription factors in the etiology of diabetes is exemplified by the fact that five of the six known forms of monogenic diabetes (MODY) result from mutations in genes encoding these factors. Recent genome-wide associations studies have identified multiple loci, or genomic regions, that are associated with type 2 diabetes; however, the mechanisms behind the associations of these new gene variants and disease have yet to be determined. This is of particular importance for a region on chromosome 10, because in this case three genes are in the same haplotype block and thus inherited together: HHEX (Hematopoietically expressed homeobox), KIF11 (kinesin-interacting factor 11) and IDE (insulin-degrading enzyme). Therefore, we will investigate the contribution of the mouse Hhex gene to endocrine pancreas differentiation and 2-cell function using genetic and genomic means. In addition, we will extend our work on transcriptional regulation of pancreatic development and function through conditional gene ablation of CREB, for which existing data are controversial. Our specific aims are: In specific Aim 1, we will determine the contribution of Hhex to pancreas development and differentiation using conditional gene ablation and genome- wide location analysis. In Aim 2, we will delineate the role of Hhex in function and proliferation of the mature 2-cell using multiple physiological, biochemical and molecular approaches. In Aim 3, we will investigate how the cAMP- responsive transcription factor CREB controls stimulus-secretion coupling and the 2-cells response to incretins using cell-type and inducible gene deletion. PUBLIC HEALTH RELEVANCE: Diabetes is a significant health problem, affecting more than 20 million people in the United States. Failure of the insulin-producing beta-cell to keep up with the body's need for insulin is a major contributor to diabates. The molecular mechanisms that regulate beta-cell proliferation and function are far from being understood completely. Therefore, we will develop and exploit new genetic tools to elucidate fundamental questions regarding the function of transcriptional regulators, or master genes, in proliferation and performance of beta-cells.